Variation in the Transcriptome Response and Detoxification Gene Diversity Drives Pesticide Tolerance in Fishes.

Pesticides are critical for invasive species management but often have negative effects on nontarget native biota. Tolerance to pesticides should have an evolutionary basis, but this is poorly understood. Invasive sea lamprey (Petromyzon marinus) populations in North America have been controlled with a pesticide lethal to them at lower concentrations than native fishes. We addressed how interspecific variation in gene expression and detoxification gene diversity confer differential pesticide sensitivity in two fish species. We exposed sea lamprey and bluegill (Lepomis macrochirus), a tolerant native species, to 3-trifluoromethyl-4-nitrophenol (TFM), a pesticide commonly used in sea lamprey control. We then used whole-transcriptome sequencing of gill and liver to characterize the cellular response in both species. Comparatively, bluegill exhibited a larger number of detoxification genes expressed and a larger number of responsive transcripts overall, which likely contributes to greater tolerance to TFM. Understanding the genetic and physiological basis for pesticide tolerance is crucial for managing invasive species.

Impact of STIMUlant and osmotic LAXatives (STIMULAX trial) on gastrointestinal recovery after colorectal surgery: randomized clinical trial.

BACKGROUND: Recovery of gastrointestinal (GI) function is often delayed after colorectal surgery. Enhanced recovery protocols (ERPs) recommend routine laxative use, but evidence of benefit is unclear. This study aimed to investigate whether the addition of multimodal laxatives to an ERP improves return of GI function in patients undergoing colorectal surgery. METHODS: This was a single-centre, parallel, open-label RCT. All adult patients undergoing elective colorectal resection or having stoma formation or reversal at the Royal Adelaide Hospital between August 2018 and May 2020 were recruited into the study. The STIMULAX group received oral Coloxyl® with senna and macrogol, with a sodium phosphate enema in addition for right-sided operations. The control group received standard ERP postoperative care. The primary outcome was GI-2, a validated composite measure defined as the interval from surgery until first passage of stool and tolerance of solid intake for 24 h in the absence of vomiting. Secondary outcomes were the incidence of prolonged postoperative ileus (POI), duration of hospital stay, and postoperative complications. The analysis was performed on an intention-to-treat basis. RESULTS: Of a total of 170 participants, 85 were randomized to each group. Median GI-2 was 1 day shorter in the STIMULAX compared with the control group (median 2 (i.q.r. 1.5-4) versus 3 (2-5.5) days; 95 per cent c.i. -1 to 0 days; P = 0.029). The incidence of prolonged POI was lower in the STIMULAX group (22 versus 38 per cent; relative risk reduction 42 per cent; P = 0.030). There was no difference in duration of hospital day or 30-day postoperative complications (including anastomotic leak) between the STIMULAX and control groups. CONCLUSION: Routine postoperative use of multimodal laxatives after elective colorectal surgery results in earlier recovery of gastrointestinal function and reduces the incidence of prolonged POI. Registration number: ACTRN12618001261202 (www.anzctr.org.au).

The Impact of the Largest National Joint Registry on Current Knee Replacement Longevity Estimates: An Analysis and Review of Knee Prosthesis Brand and Fixation Technique.

BACKGROUND: The UK National Joint Registry is the single largest joint registry in the world enrolling 1.3 million patients and recently reaching 17 years of follow-up data. Current knee prosthesis longevity estimates are based off smaller sized international registries and the impact of fixation type on prosthesis survival remains unclear. METHODS: We used the UK National Joint Registry 17th annual report to calculate pooled mean survival estimates of total knee replacements (TKRs), unicondylar knee replacements (UKRs), and patellofemoral knee replacements at 10 and 15 years based on both construct brand and fixation technique (cemented vs uncemented). Independent t-testing was performed for significance. RESULTS: All-cause survivorship of TKRs at 10 and 15 years is 96.7% and 95.4%, respectively. For UKRs it is 89.8% and 80.7% and for patellofemoral knee replacements it is 81.6% and 76.5%. In regard to fixation technique, cemented and uncemented TKRs show similar survivorship at both time points. For UKRs uncemented constructs showed improved survivorship compared to cemented at 10 years (92.7% vs 88.2%, P < .001). This was greatest among those <65 years of age. In fact, all construct types regardless of fixation showed increased rate of revision in those <65 years vs those ≥65 years. CONCLUSION: We provide more accurate estimations for knee prosthesis survival and highlight that younger patients, particularly those receiving UKRs, are prone to greater revision risks. This data also suggests that uncemented fixation may offer improved joint survival in these patients.

Stratum corneum lipid matrix: Location of acyl ceramide and cholesterol in the unit cell of the long periodicity phase.

The extracellular lipid matrix in the skin's outermost layer, the stratum corneum, is crucial for the skin barrier. The matrix is composed of ceramides (CERs), cholesterol (CHOL) and free fatty acids (FFAs) and involves two lamellar phases: the short periodicity phase (SPP) and the long periodicity phase (LPP). To understand the skin barrier thoroughly, information about the molecular arrangement in the unit cell of these lamellar phases is paramount. Previously we examined the molecular arrangement in the unit cell of the SPP. Furthermore X-ray and neutron diffraction revealed a trilayer arrangement of lipids within the unit cell of the LPP [D. Groen et al., Biophysical Journal, 97, 2242-2249, 2009]. In the present study, we used neutron diffraction to obtain more details about the location of lipid (sub)classes in the unit cell of the LPP. The diffraction pattern revealed at least 8 diffraction orders of the LPP with a repeating unit of 129.6±0.5Å. To determine the location of lipid sub(classes) in the unit cell, samples were examined with either only protiated lipids or selectively deuterated lipids. The diffraction data obtained by means of D2O/H2O contrast variation together with a gradual replacement of one particular CER, the acyl CER, by its partly deuterated counterpart, were used to construct the scattering length density profiles. The acyl chain of the acyl CER subclass is located at a position of ~21.4±0.2Å from the unit cell centre of the LPP. The position and orientation of CHOL in the LPP unit cell were determined using tail and head-group deuterated forms of the sterol. CHOL is located with its head-group positioned ~26±0.2Å from the unit cell centre. This allows the formation of a hydrogen bond with the ester group of the acyl CER located in close proximity. Based on the positions of the deuterated moieties of the acyl CER, CHOL and the previously determined location of two other lipid subclasses [E.H. Mojumdar et al., Biophysical Journal, 108, 2670-2679, 2015], a molecular model is proposed for the unit cell of the LPP. In this model CHOL is located in the two outer layers of the LPP, while CER EOS is linking the two outer layers with the central lipid layers. Finally the two other lipid subclasses are predominantly located in the central layer of the LPP.

A simple web-based risk calculator (www.anastomoticleak.com) is superior to the surgeon's estimate of anastomotic leak after colon cancer resection.

BACKGROUND: Anastomotic leak can be a devastating complication, and early prediction is difficult. The aim of this study is to prospectively validate a simple anastomotic leak risk calculator and compare its predictive value with the estimate of the primary operating surgeon. METHODS: Consecutive patients undergoing elective or emergency colon cancer surgery with a primary anastomosis over a 1-year period were prospectively included. A recently published anastomotic leak risk nomogram was converted to an online calculator ( www.anastomoticleak.com ). The calculator-derived risk of anastomotic leak and the risk estimated by the primary operating surgeon were recorded at the completion of surgery. The primary outcome was anastomotic leak within 90 days as defined by previously published criteria. Area under receiver operating characteristic curve analysis (AUROC) was performed for both risk estimates. RESULTS: A total of 105 patients were screened for inclusion during the study period, of whom 83 met the inclusion criteria. The overall anastomotic leak rate was 9.6%. The anastomotic leak calculator was highly predictive of anastomotic leak (AUROC 0.84, P = 0.002), whereas the surgeon estimate was not predictive (AUROC 0.40, P = 0.243). CONCLUSIONS: A simple anastomotic leak risk calculator is significantly better at predicting anastomotic leak than the estimate of the primary surgeon. Further external validation on a larger data set is required.

Validation of an online risk calculator for the prediction of anastomotic leak after colon cancer surgery and preliminary exploration of artificial intelligence-based analytics.

BACKGROUND: Recently published data support the use of a web-based risk calculator ( www.anastomoticleak.com ) for the prediction of anastomotic leak after colectomy. The aim of this study was to externally validate this calculator on a larger dataset. METHODS: Consecutive adult patients undergoing elective or emergency colectomy for colon cancer at a single institution over a 9-year period were identified using the Binational Colorectal Cancer Audit database. Patients with a rectosigmoid cancer, an R2 resection, or a diverting ostomy were excluded. The primary outcome was anastomotic leak within 90 days as defined by previously published criteria. Area under receiver operating characteristic curve (AUROC) was derived and compared with that of the American College of Surgeons National Surgical Quality Improvement Program® (ACS NSQIP) calculator and the colon leakage score (CLS) calculator for left colectomy. Commercially available artificial intelligence-based analytics software was used to further interrogate the prediction algorithm. RESULTS: A total of 626 patients were identified. Four hundred and fifty-six patients met the inclusion criteria, and 402 had complete data available for all the calculator variables (126 had a left colectomy). Laparoscopic surgery was performed in 39.6% and emergency surgery in 14.7%. The anastomotic leak rate was 7.2%, with 31.0% requiring reoperation. The anastomoticleak.com calculator was significantly predictive of leak and performed better than the ACS NSQIP calculator (AUROC 0.73 vs 0.58) and the CLS calculator (AUROC 0.96 vs 0.80) for left colectomy. Artificial intelligence-predictive analysis supported these findings and identified an improved prediction model. CONCLUSIONS: The anastomotic leak risk calculator is significantly predictive of anastomotic leak after colon cancer resection. Wider investigation of artificial intelligence-based analytics for risk prediction is warranted.

Stress, nutrition and parental care in a teleost fish: exploring mechanisms with supplemental feeding and cortisol manipulation.

Parental care is an essential life-history component of reproduction for many animal species, and it entails a suite of behavioural and physiological investments to enhance offspring survival. These investments can incur costs to the parent, reducing their energetic and physiological condition, future reproductive capabilities and survival. In fishes, relatively few studies have focused on how these physiological costs are mediated. Male smallmouth bass provide parental care for developing offspring until the brood reaches independence. During this energetically demanding life stage, males cease active foraging as they vigorously defend their offspring. Experimental manipulation of cortisol levels (via implantation) and food (via supplemental feeding) in parental males was used to investigate the fitness consequences of parental care. Improving the nutritional condition of nest-guarding males increased their reproductive success by reducing premature nest abandonment. However, supplemental feeding and cortisol treatment had no effect on parental care behaviours. Cortisol treatment reduced plasma lymphocyte numbers, but increased neutrophil and monocyte concentrations, indicating a shift in immune function. Supplemental feeding improved the physiological condition of parental fish by reducing the accumulation of oxidative injury. Specifically, supplemental feeding reduced the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) on DNA nucleotides. Increasing the nutritional condition of parental fish can reduce the physiological cost associated with intensive parental activity and improve overall reproductive success, illustrating the importance of nutritional condition as a key modulator of parental fitness.

Laparoscopic versus open gastrectomy for gastric cancer.

BACKGROUND: Gastric cancer is the third most common cause of cancer-related mortality in the world. Currently there are two surgical options for potentially curable patients (i.e. people with non-metastatic gastric cancer), laparoscopic and open gastrectomy. However, it is not clear whether one of these options is superior. OBJECTIVES: To assess the benefits and harms of laparoscopic gastrectomy or laparoscopy-assisted gastrectomy versus open gastrectomy for people with gastric cancer. In particular, we planned to investigate the effects by patient groups, such as cancer stage, anaesthetic risk, and body mass index (BMI), and by intervention methods, such as method of anastomosis, type of gastrectomy and laparoscopic or laparoscopically-assisted gastrectomy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index, ClinicalTrials.gov and the WHO ICTRP (World Health Organization International Clinical Trials Registry Platform) until September 2015. We also screened reference lists from included trials. SELECTION CRITERIA: Two review authors independently selected references for further assessment by going through all titles and abstracts. Further selection was based on review of full text articles for selected references. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study data. We calculated the risk ratio (RR) with 95% confidence interval (CI) for binary outcomes, the mean difference (MD) or the standardised mean difference (SMD) with 95% CI for continuous outcomes and the hazard ratio (HR) for time-to-event outcomes. We performed meta-analyses where it was meaningful. MAIN RESULTS: In total, 2794 participants were randomised in 13 trials included in this review. All the trials were at unclear or high risk of bias. One trial (which included 53 participants) did not contribute any data to this review. A total of 213 participants were excluded in the remaining trials after randomisation, leaving a total of 2528 randomised participants for analysis, with 1288 undergoing laparoscopic gastrectomy and 1240 undergoing open gastrectomy. All the participants were suitable for major surgery.There was no difference in the proportion of participants who died within thirty days of treatment between laparoscopic gastrectomy (7/1188: adjusted proportion = 0.6% (based on meta-analysis)) and open gastrectomy (4/1447: 0.3%) (RR 1.60, 95% CI 0.50 to 5.10; risk difference 0.00, 95% CI -0.01 to 0.01; participants = 2335; studies = 11; I(2) = 0%; low quality evidence). There were no events in either group for short-term recurrence (participants = 103; studies = 3), proportion requiring blood transfusion (participants = 66; studies = 2), and proportion with positive margins at histopathology (participants = 28; studies = 1). None of the trials reported health-related quality of life, time to return to normal activity or time to return to work. The differences in long-term mortality (HR 0.94, 95% CI 0.70 to 1.25; participants = 195; studies = 3; I(2) = 0%; very low quality evidence), serious adverse events within three months (laparoscopic gastrectomy (7/216: adjusted proportion = 3.6%) versus open gastrectomy (13/216: 6%) (RR 0.60, 95% CI 0.27 to 1.34; participants = 432; studies = 8; I(2) = 0%; very low quality evidence), long-term recurrence (HR 0.95, 95% CI 0.70 to 1.30; participants = 162; studies = 4; very low quality evidence), adverse events within three months (laparoscopic gastrectomy (204/268: adjusted proportion = 16.1%) versus open gastrectomy (253/1222: 20.7%) (RR 0.78, 95% CI 0.60 to 1.01; participants = 2490; studies = 11; I(2) = 38%; very low quality evidence), quantity of perioperative blood transfused (SMD 0.05, 95% CI -0.27 to 0.38; participants = 143; studies = 2; I(2) = 0%; very low quality evidence), length of hospital stay (MD -1.82 days, 95% CI -3.72 to 0.07; participants = 319; studies = 6; I(2) = 83%; very low quality evidence), and number of lymph nodes harvested (MD -0.63, 95% CI -1.51 to 0.25; participants = 472; studies = 9; I(2) = 40%; very low quality evidence) were imprecise. There was no alteration in the interpretation of the results in any of the subgroups. AUTHORS' CONCLUSIONS: Based on low quality evidence, there is no difference in short-term mortality between laparoscopic and open gastrectomy. Based on very low quality evidence, there is no evidence for any differences in short-term or long-term outcomes between laparoscopic and open gastrectomy. However, the data are sparse, and the confidence intervals were wide, suggesting that significant benefits or harms of laparoscopic gastrectomy cannot be ruled out. Several trials are currently being conducted and interim results of these trials have been included in this review. These trials need to perform intention-to-treat analysis to ensure that the results are reliable and report the results according to the CONSORT Statement.

Non-surgical versus surgical treatment for oesophageal cancer.

BACKGROUND: Oesophageal cancer is the sixth most common cause of cancer-related mortality in the world. Currently surgery is the recommended treatment modality when possible. However, it is unclear whether non-surgical treatment options is equivalent to oesophagectomy in terms of survival. OBJECTIVES: To assess the benefits and harms of non-surgical treatment versus oesophagectomy for people with oesophageal cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to 4th March 2016. We also screened reference lists of included studies. SELECTION CRITERIA: Two review authors independently screened all titles and abstracts of articles obtained from the literature searches and selected references for further assessment. For these selected references, we based trial inclusion on assessment of the full-text articles. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study data. We calculated the risk ratio (RR) with 95% confidence interval (CI) for binary outcomes, the mean difference (MD) or the standardised mean difference (SMD) with 95% CI for continuous outcomes, and the hazard ratio (HR) for time-to-event outcomes. We performed meta-analyses where it was meaningful. MAIN RESULTS: Eight trials, which included 1132 participants in total, met the inclusion criteria of this Cochrane review. These trials were at high risk of bias trials. One trial (which included five participants) did not contribute any data to this Cochrane review, and we excluded 13 participants in the remaining trials after randomisation; this left a total of 1114 participants, 510 randomised to non-surgical treatment and 604 to surgical treatment for analysis. The non-surgical treatment was definitive chemoradiotherapy in five trials and definitive radiotherapy in three trials. All participants were suitable for major surgery. Most of the data were from trials that compared chemoradiotherapy with surgery. There was no difference in long-term mortality between chemoradiotherapy and surgery (HR 0.88, 95% CI 0.76 to 1.03; 602 participants; four studies; low quality evidence). The long-term mortality was higher in radiotherapy than surgery (HR 1.39, 95% CI 1.18 to 1.64; 512 participants; three studies; very low quality evidence). There was no difference in long-term recurrence between non-surgical treatment and surgery (HR 0.96, 95% CI 0.80 to 1.16; 349 participants; two studies; low quality evidence). The difference between non-surgical and surgical treatments was imprecise for short-term mortality (RR 0.39, 95% CI 0.11 to 1.35; 689 participants; five studies; very low quality evidence), the proportion of participants with serious adverse in three months (RR 0.61, 95% CI 0.25 to 1.47; 80 participants; one study; very low quality evidence), and proportion of people with local recurrence at maximal follow-up (RR 0.89, 95% CI 0.70 to 1.12; 449 participants; three studies; very low quality evidence). The health-related quality of life was higher in non-surgical treatment between four weeks and three months after treatment (Spitzer Quality of Life Index; MD 0.93, 95% CI 0.24 to 1.62; 165 participants; one study; very low quality evidence). The difference between non-surgical and surgical treatments was imprecise for medium-term health-related quality of life (three months to two years after treatment) (Spitzer Quality of Life Index; MD -0.95, 95% CI -2.10 to 0.20; 62 participants; one study; very low quality of evidence). The proportion of people with dysphagia at the last follow-up visit prior to death was higher with definitive chemoradiotherapy compared to surgical treatment (RR 1.48, 95% CI 1.01 to 2.19; 139 participants; one study; very low quality evidence). AUTHORS' CONCLUSIONS: Based on low quality evidence, chemoradiotherapy appears to be at least equivalent to surgery in terms of short-term and long-term survival in people with oesophageal cancer (squamous cell carcinoma type) who are fit for surgery and are responsive to induction chemoradiotherapy. However, there is uncertainty in the comparison of definitive chemoradiotherapy versus surgery for oesophageal cancer (adenocarcinoma type) and we cannot rule out significant benefits or harms of definitive chemoradiotherapy versus surgery. Based on very low quality evidence, the proportion of people with dysphagia at the last follow-up visit prior to death was higher with definitive chemoradiotherapy compared to surgery. Based on very low quality evidence, radiotherapy results in less long-term survival than surgery in people with oesophageal cancer who are fit for surgery. However, there is a risk of bias and random errors in these results, although the risk of bias in the studies included in this systematic review is likely to be lower than in non-randomised studies.Further trials at low risk of bias are necessary. Such trials need to compare endoscopic treatment with surgical treatment in early stage oesophageal cancer (carcinoma in situ and Stage Ia), and definitive chemoradiotherapy with surgical treatments in other stages of oesophageal cancer, and should measure and report patient-oriented outcomes. Early identification of responders to chemoradiotherapy and better second-line treatment for non-responders will also increase the need and acceptability of trials that compare definitive chemoradiotherapy with surgery.

Neutron Scattering Studies of the Effects of Formulating Amphotericin B with Cholesteryl Sulfate on the Drug's Interactions with Phospholipid and Phospholipid-Sterol Membranes.

Langmuir surface pressure, small-angle neutron scattering (SANS), and neutron reflectivity (NR) studies have been performed to determine how formulation of the antifungal drug amphotericin B (AmB), with sodium cholesteryl sulfate (SCS)-as in Amphotec-affects its interactions with ergosterol-containing (model fungal cell) and cholesterol-containing (model mammalian cell) membranes. The effects of mixing AmB in 1:1 molar ratio with cholesteryl sulfate (yielding AmB-SCS micelles) are compared against those of free AmB, using monolayers and bilayers formed from palmitoyloleoylphosphatidylcholine (POPC) in the absence and presence of 30 mol % ergosterol or cholesterol, in all cases employing a 1:0.05 molar ratio of lipid:AmB. Analyses of the (bilayer) SANS and (monolayer) NR data indicate that the equilibrium changes in membrane structure induced in sterol-free and sterol-containing membranes are the same for free AmB and AmB-SCS. Stopped-flow SANS experiments, however, reveal that the structural changes to vesicle membranes occur far more rapidly following exposure to AmB-SCS vs free drug, with the kinetics of these changes varying with membrane composition. With POPC vesicles, the structural changes induced by AmB-SCS become apparent only after several minutes, and equilibrium is reached after ∼30 min. The corresponding onset of changes in POPC-ergosterol and POPC-cholesterol vesicles, however, occurs within ∼5 s, with equilibrium reached after 10 and 120 s, respectively. The rate of insertion of AmB into POPC-sterol membranes is thus increased through formulation as AmB-SCS. Moreover, the differences in monolayer surface pressure and SANS structure-change equilibration times suggest significant rearrangement of AmB within these membranes following insertion. The reduced times to equilibrium for the POPC-ergosterol vs POPC-cholesterol systems are consistent with the known differences in affinity of AmB for these two sterols, and the reduced time to equilibrium for AmB-SCS interaction with POPC-ergosterol membranes vs that for free AmB is consistent with the reduced host toxicity of Amphotec.

Interaction of amphotericin B with lipid monolayers.

Langmuir isotherm, neutron reflectivity, and Brewster angle microscopy experiments have been performed to study the interaction of amphotericin B (AmB) with monolayers prepared from 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) and mixtures of this lipid with cholesterol or ergosterol to mimic mammalian and fungal cell membranes, respectively. Isotherm data show that AmB causes a more pronounced change in surface pressure in the POPC/ergosterol system than in the POPC and POPC/cholesterol systems, and its interaction with the POPC/ergosterol monolayer is also more rapid than with the POPC and POPC/cholesterol monolayers. Brewster angle microscopy shows that, in interaction with POPC monolayers, AmB causes the formation of small domains which shrink and disappear within a few minutes. The drug also causes domain formation in the POPC/cholesterol and POPC/ergosterol monolayers; in the former case, these are formed more slowly than is seen with the POPC monolayers and are ultimately much smaller; in the latter case, they are formed rather more quickly and are more heterogeneous in size. Neutron reflectivity data show that the changes in monolayer structure following interaction with AmB are the same for all three systems studied: the data are consistent with the drug inserting into the monolayers with its macrocyclic ring intercalated among the lipid acyl chains and sterol ring systems, with its mycosamine moiety colocalizing with the sterol hydroxyl and POPC head groups. On the basis of these studies, it is concluded that AmB inserts in a similar manner into POPC, POPC/cholesterol, and POPC/ergosterol monolayers but does so with differing kinetics and with the formation of quite different in-plane structures. The more rapid time scale for interaction of the drug with the POPC/ergosterol monolayer, its more pronounced effect on monolayer surface pressure, and its more marked changes as regards domain formation are all consistent with the drug's selectivity for fungal vs mammalian cell membranes.

Localization of cholesterol and fatty acid in a model lipid membrane: a neutron diffraction approach.

The intercellular lipid matrix of the skin's stratum corneum serves to protect the body against desiccation and simultaneously limits the passage of drugs and other xenobiotics into the body. The matrix is made up of ceramides, free fatty acids, and cholesterol, which are organized as two coexisting crystalline lamellar phases. In studies reported here, we sought to use the technique of neutron diffraction, together with the device of isotopic (H/D) substitution, to determine the molecular architecture of the lamellar phase having a repeat distance of 53.9 ± 0.3 Å. Using hydrogenous samples as well as samples incorporating perdeuterated (C24:0) fatty acids and selectively deuterated cholesterol, the diffraction data obtained were used to construct neutron scattering length density profiles. By this means, the locations within the unit cell were determined for the cholesterol and fatty acids. The cholesterol headgroup was found to lie slightly inward from the unit cell boundary and the tail of the molecule located 6.2 ± 0.2 Å from the unit cell center. The fatty acid headgroups were located at the unit cell boundary with their acyl chains straddling the unit cell center. Based on these results, a molecular model is proposed for the arrangement of the lipids within the unit cell.

Freshwater protected areas can preserve high-performance phenotypes in populations of a popular sportfish.

Recreational fishing has the potential to cause evolutionary change in fish populations; a phenomenon referred to as fisheries-induced evolution. However, detecting and quantifying the magnitude of recreational fisheries selection in the wild is inherently difficult, largely owing to the challenges associated with variation in environmental factors and, in most cases, the absence of pre-selection or baseline data against which comparisons can be made. However, exploration of recreational fisheries selection in wild populations may be possible in systems where fisheries exclusion zones exist. Lakes that possess intra-lake freshwater protected areas (FPAs) can provide investigative opportunities to evaluate the evolutionary impact(s) of differing fisheries management strategies within the same waterbody. To address this possibility, we evaluated how two physiological characteristics (metabolic phenotype and stress responsiveness) as well as a proxy for angling vulnerability, catch-per-unit-effort (CPUE), differed between populations of largemouth bass (Micropterus salmoides) inhabiting long-standing (>70 years active) intra-lake FPAs and adjacent, open access, main-lake areas. Fish from FPA populations had significantly higher aerobic scope (AS) capacity (13%) and CPUE rates compared with fish inhabiting the adjacent main-lake areas. These findings are consistent with theory and empirical evidence linking exploitation with reduced metabolic performance, supporting the hypothesis that recreational fishing may be altering the metabolic phenotype of wild fish populations. Reductions in AS are concerning because they suggest a reduced scope for carrying out essential life-history activities, which may result in fitness level implications. Furthermore, these results highlight the potential for unexploited FPA populations to serve as benchmarks to further investigate the evolutionary consequences of recreational fishing on wild fish and to preserve high-performance phenotypes.

Role of Ursodeoxycholic Acid in the Prevention of Gallstones Formation in Bariatric Patients-a Systematic Review and Meta-Analysis of Randomised Trials.

The aim of this meta-analysis was to assess whether treatment with ursodeoxycholic acid (UDCA) in patients who have undergone bariatric surgery reduces gallstone formation. A systematic literature search was performed using electronic databases (MEDLINE, Embase, CENTRAL, Web of Science, PROSPERO, Google Scholar and the WHO International Clinical Trials Registry platform). RCTs without restrictions on study language, year, status of publication and patient's age were used. Pooled risk ratios were calculated using a random-effects model. Subgroup analyses for drug dose, duration and procedure types were performed. Sensitivity analyses and a summary of findings table were generated to assess the robustness and the level of evidence provided, respectively. Fourteen trials were included (3619 patients, 2292 in UDCA vs 1327 in control group). Procedures included SG, RYGB, OAGB, AGB and Gastroplasty. UDCA dose ranged from 300 to 1200 mg per day. Gallstone formation occurred in 19.3% (8.3% in UDCA vs 38.1% in the control group). UDCA significantly reduced the risk of gallstone formation (14 trials, 3619 patients; RR 0.27, 95% CI 0.18-0.41; P < 0.001). UDCA significantly reduced the risk of symptomatic gallstone disease (6 trials, 2458 patients; RR 0.30, 95% CI 0.21-0.43; P < 0.001). No subgroup difference was found for different doses, duration and type of procedure performed. Oral UDCA treatment significantly reduces the risks of developing gallstones in postoperative bariatric patients from 38 to 8%. The use of 500 to 600 mg UDCA for 6 months is effective and should be implemented in all patients post-bariatric surgery.

Differences in the transcriptome response in the gills of sea lamprey acutely exposed to 3-trifluoromethyl-4-nitrophenol (TFM), niclosamide or a TFM:niclosamide mixture.

Sea lamprey (Petromyzon marinus) control in the Laurentian Great Lakes of North America makes use of two pesticides: 3-trifluoromethyl-4-nitrophenol (TFM) and niclosamide, which are often co-applied. Sea lamprey appear to be vulnerable to these agents resulting from a lack of detoxification responses with evidence suggesting that lampricide mixtures produce a synergistic effect. However, there is a lack of information pertaining to the physiological responses of sea lamprey to niclosamide and TFM:niclosamide mixtures. Here, we characterized the transcriptomic responses of the sea lamprey to TFM, niclosamide, and a TFM:niclosamide (1.5 %) mixture in the gill. Along with a control, larval sea lamprey were exposed to each treatment for 6 h, after which gill tissues were extracted for measuring whole-transcriptome responses using RNA sequencing. Differential gene expression patterns were summarized, which included identifying the broad roles of genes and common expression patterns among the treatments. While niclosamide treatment resulted in no differentially expressed genes, TFM- and mixture-treated fish had several differentially expressed genes that were associated with the cell cycle, DNA damage, metabolism, immune function, and detoxification. However, there was no common differential expression among treatments. For the first time, we characterized the transcriptomic response of sea lamprey to niclosamide and a TFM:niclosamide mixture and identified that these agents impact mRNA transcript abundance of genes associated with the cell cycle and cellular death, and immune function, which are likely mediated through mitochondrial dysregulation. These results may help to inform the production of more targeted and effective lampricides in sea lamprey control efforts.

Transcriptomic impacts and potential routes of detoxification in a lampricide-tolerant teleost exposed to TFM and niclosamide.

Sea lamprey (Petromyzon marinus) control in the Laurentian Great Lakes of North America often relies on the application of 3-trifluoromethyl-4-nitrophenol (TFM) and niclosamide mixtures to kill larval sea lamprey. Selectivity of TFM against lampreys appears to be due to differential detoxification ability in these jawless fishes compared to bony fishes, particularly teleosts. However, the proximate mechanisms of tolerance to the TFM and niclosamide mixture and the mechanisms of niclosamide toxicity on its own are poorly understood, especially among non-target fishes. Here, we used RNA sequencing to identify specific mRNA transcripts and functional processes that responded to niclosamide or a TFM:niclosamide mixture in bluegill (Lepomis macrochirus). Bluegill were exposed to niclosamide or TFM:niclosamide mixture, along with a time-matched control group, and gill and liver tissues were sampled at 6, 12, and 24 h. We summarized the whole-transcriptome patterns through gene ontology (GO) term enrichment and through differential expression of detoxification genes. The niclosamide treatment resulted in an upregulation of several transcripts associated with detoxification (cyp, ugt, sult, gst), which may help explain the relatively high detoxification capacity in bluegill. Conversely, the TFM:niclosamide mixture resulted in an enrichment of processes related to arrested cell cycle and growth, and cell death alongside a diverse detoxification gene response. Detoxification of both lampricides likely involves the use of phase I and II biotransformation genes. Our findings strongly suggest that the unusually high tolerance of bluegill to lampricides is due to these animals having an inherently high capacity and flexible detoxification response to such compounds.

A Systematic Review of Patient Race, Ethnicity, Socioeconomic Status, and Educational Attainment in Prostate Cancer Treatment Randomised Trials-Is the Evidence Base Applicable to the General Patient Population?

Context: Prostate cancer (PC) disproportionately affects men of Black race, and lower educational and socioeconomic status. Guidelines are based on randomised controlled trials (RCTs); however, the representation of different races, educations, and socioeconomic backgrounds in these trials is unclear. Objective: To assess reporting of equality, diversity, and inclusion characteristics (Equality, Diversity and Inclusion [EDI]) and differences in treatment effects between different races, and educational or socioeconomic status. Evidence acquisition: We conducted a systematic review of CENTRAL, MEDLINE, and Embase in April 2020 examining RCTs investigating treatments for PC. Outcomes collected were race/ethnicity, educational attainment, and socioeconomic status. RCTs investigating PC treatment in any population or setting were included. Data extraction of characteristics was performed independently by pairs of reviewers and checked by a senior author. The Cochrane risk of bias tool assessed the quality of included papers. Evidence synthesis: A total of 265 trials were included, and 138 of these were available as full-text articles. Fifty-four trials including 19 039 participants reported any EDI data. All 54 trials reported race, 11 reported ethnicity, three reported educational attainment, and one reported socioeconomic status. Patients of White race were the majority of the recruited population (82.6%), while the minority prevalence was as follows: Black 9.8% and Asian 5.7%. Three studies reported mortality outcomes depending on the participant's race. All three studies investigated different treatments, so a meta-analysis was not performed. No studies reported outcomes stratified by the educational or socioeconomic status of participants. Conclusions: There is poor reporting of patient race, ethnicity, socioeconomic background, and educational attainment in RCTs for PC treatments between 2010 and 2020. Addressing this for future studies will help explain differences in the incidence of and mortality from PC and improve the generalisability of results. Patient summary: In this study, we reviewed prostate cancer treatment trials to see whether these reported race, education, and socioeconomic backgrounds of their patient populations. We conclude that reporting of these characteristics is poor. This needs to be improved in future to improve outcomes for patients with prostate cancer of all ethnical, racial, and socioeconomic groups.

Small-angle neutron scattering studies of the effects of amphotericin B on phospholipid and phospholipid-sterol membrane structure.

Small-angle neutron scattering (SANS) studies have been performed to study the structural changes induced in the membranes of vesicles prepared (by thin film evaporation) from phospholipid and mixed phospholipid-sterol mixtures, in the presence of different concentrations and different aggregation states of the anti-fungal drug, amphotericin B (AmB). In the majority of the experiments reported, the lipid vesicles were prepared with the drug added directly to the lipid dispersions dissolved in solvents favouring either AmB monomers or aggregates, and the vesicles then sonicated to a mean size of ~100 nm. Experiments were also performed, however, in which micellar dispersions of the drug were added to pre-formed lipid and lipid-sterol vesicles. The vesicles were prepared using the phospholipid palmitoyloleoylphosphatidylcholine (POPC), or mixtures of this lipid with either 30 mol% cholesterol or 30 mol% ergosterol. Analyses of the SANS data show that irrespective of the AmB concentration or aggregation state, there is an increase in the membrane thickness of both the pure POPC and the mixed POPC-sterol vesicles-in all cases amounting to ~4 Å. The structural changes induced by the drug's insertion into the model fungal cell membranes (as mimicked by POPC-ergosterol vesicles) are thus the same as those resulting from its insertion into the model mammalian cell membranes (as mimicked by POPC-cholesterol vesicles). It is concluded that the specificity of AmB for fungal versus human cells does not arise because of (static) structural differences between lipid-cholesterol-AmB and lipid-ergosterol-AmB membranes, but more likely results from differences in the kinetics of their transmembrane pore formation and/or because of enthalpic differences between the two types of sterol-AmB complexes.